1. Technical Field
The field of this invention is the treatment of pain, particularly surgically caused or other type of wound.
2. Background of the Invention
In the management of post-operative pain, several kinds of drugs are widely used, amongst them local anesthetics and systemic opioids. Local anesthetics reversibly block the impulse conduction along nerves and other excitable membranes that primarily utilize sodium channels. Clinically, this action blocks sensation from specific areas of the body.
Surgery, whether by invasive procedures, e.g. resection, laparoscopy, or other operation resulting in penetration of the outer surface of a body part with the involvement of nerves, frequently leads to pain. With a growing emphasis on rapid return to function and out-patient surgery, the management of post-operative pain is receiving ever greater emphasis. Local anesthetics have found extensive use, but are usually short lived. Local anesthetic pumps and catheters are cumbersome and can suffer from inadequate distribution throughout the wound. In order to diminish post-operative pain, pain-killing medications, usually opioids, are prescribed. These untargeted medications affect all of the body, while only the portion involved surgically requires treatment. Other affected body systems are typically impacted adversely such as in constipation, nausea, respiratory depression, sedation, and confusion. It is therefore of great importance that methods be found to control surgical pain for extended periods of time at the site of surgery while minimizing the adverse impact on other bodily functions.
Local anesthetics of the “caine” family are weak bases. (By “caine” is intended anesthetics that end in the suffix caine, which will usually include amino acid amides and esters.) One of the classes of anesthetics that are amine bases also includes an aromatic ring, for example, a meta-xylyl group and an amide or ester functionality. The aromatic group with the other entities results in hydrophobicity, so that the members of the class are frequently employed as their hydrochloride salts to allow for water solubility. Examples of such anesthetics of the caine family include lidocaine (lignocaine), procaine, bupivacaine, ropivacaine, butacaine oxybuprocaine mepivacaine, prilocaine, amylocaine chloroprocaine, etidocaine, propoxycaine and tropacocaine. Local anesthetics are usually administered by injection into the area of the nerve fibers to be blocked. Thus, absorption and distribution are not as important in controlling the onset of effect as in determining the rate of offset of anesthesia and the likelihood of central nervous system and cardiac toxicity. Topical application of local anesthetics, where there is an intact skin barrier requires drug diffusion for both onset and offset of anesthetic effect. Therefore, the solubility and stability of the drug become major factors in determining the therapeutic effects of the drug. (Miller & Hondeghem, (1995), “Local Anesthetics” in Basic & Clinical Pharmacology, 6.sup.th Edition, Ed. by Katzung).
Among the local anesthetics, lidocaine, 2-(diethylamino)-N-(2,6-dimethylphenyl)-acetamide, in addition to its widespread use as a local anesthetic, is particularly known for its treatment of ventricular tachycardia (an arrythmia of the heart) as an intravenous injection solution. (See e.g., U.S. Pat. No. 3,968,205). Lidocaine is also used with vasoconstrictors to reduce regional blood flow in topical applications or aerosols (such as nasal aerosols to reduce nasal congestion). (See for example, U.S. Pat. No. 5,534,242). [In addition, lidocaine is known for its therapeutic effects in reducing post-herpetic neuralgia (PHN) nerve injury pain from shingles (herpes zoster and post herpetic neuralgia) and analogous neuropathies. For example, U.S. Pat. No. Re 37,727 discloses methods employing lidocaine intradermal administration by transport of lidocaine from the skin surface, using patches and dressings, into the skin.
Lidocaine base is freely lipid soluble. It is insoluble in water and thus not suitable for use in an aqueous solution, requiring ethanol or the like to obtain a liquid solution. However, its salt form, lidocaine-HCl, is very soluble in water and alcohol. Thus, lidocaine-HCl is the form that is used for preparation of injection solutions. However, for transdermal administration the hydrophilicity of the lidocaine hydrochloride salt inhibits transport across the skin. Furthermore, the action of the lidocaine salt can be short-lived, requiring repeated administrations to relieve the patient.
Other members of the caine family that have found extensive use are bupivacaine and ropivacaine, which find numerous studies in the scientific literature and references in the patent literature. For bupivacaine, see, for example, U.S. Pat. Nos. 6,699,908, 6,534,081, 6,521,259, 6,514,516, and 6,391,888, while in the scientific literature, Lambert et al. 2007 Arthritis Rheum 56, 2278-87; Ostergaard et al 2005 Eur J Pharm Sci 76, 280-7; and Larsen et al 2007 Eur J Pharm Sci 31, 172-9, as indicative of some of the activity in the field. Similarly, for ropivacaine, see, for example, U.S. Pat. Nos. 5,670,524, 5,834,489 and 2002/0156101, while in the scientific literature, see Polglase, et al 2007 Dis Colon Rectum, ePublication 10/3; Bariskaner, et al 2007 Methods Find Exp Clin Pharmacol 29, 337-11 and Brodner, et al 2007 Anesth Analg 105, 256-62. These anesthetics have been extensively reported in the manner in which they are administered, the particular context in which they are used and the companion drugs that are employed.
For slow release, extended anesthetic effects, and maintaining localized administration and/or minimizing toxicity, two different approaches have been employed, either individually or in combination, using a polymeric matrix or adjunctive compounds that extend the effective lifetime of the anesthetic. Neither of these approaches has proven to be entirely satisfactory in a medical setting due to the persistence of the polymeric matrix in the healing wound region and the difficulty of applying injectable formulations to broad surface and sub-surface areas of innervation associated with the surgical site. A simple effective method for providing extended pain relief is needed.
Examples of patents and patent applications that use polymeric matrices include U.S. Pat. No. 6,750,291 (Transdermal agent, film forming polyurethane and addition polymer); U.S. Pat. No. 6,699,908 (Bupivacaine in a controlled release polymeric vehicle); U.S. Pat. Nos. 6,534,081 (6,521,259) (6,514,516) (Bupivacaine in a controlled release polymeric vehicle and augmenting agent); U.S. Pat. No. 6,217,911 (Sustained release lidocaine with capped and uncapped PLGA); U.S. Pat. No. 6,086,863 (Microspheres non-biodegradable charged, insoluble in carrier plus pharmaceutical agent); U.S. Pat. No. 5,810,786 (Lidocaine in thermoplastic resin (not PLGA)); U.S. Pat. No. 5,292,512 (Microspheres of PLGA with active ingredient of 3-10 mgs); 2005/0002996 (Cellulose impregnated with drug, coated with polymer or fatty acid); and 2004/0076671 (Lidocaine in carrier applied to wound, also includes an antibiotic and wax matrix).
Examples of patents and patent applications that use adjuvants to enhance effectiveness include U.S. Pat. No. 7,166,641 (Diclofenac salt of lidocaine, pain relief of wounds); U.S. Pat. No. 6,645,521 (Surgically closed wounds treated with any anesthetic with oleic acid as penetration enhancer); U.S. Pat. No. 6,495,602 (Urea-includes lidocaine and acceptable salt; enhances efficacy of lidocaine); U.S. Pat. No. 6,429,228 (Lidocaine, alkanol of 2-3 carbon atoms and 8-18 carbon carboxylic acid as penetration enhancer); U.S. Pat. No. 6,426,339 (Glucocorticosteroids to extend local anesthesia); U.S. Pat. No. 6,255,502 (Lidocaine-bile acid salt for transdermal treatment); U.S. Pat. No. 6,238,702 (Local anesthetic in biodegradable controlled release with glucosteroid); U.S. Pat. No. 5,912,271 (Analgesic and polar lipid, e.g. sphingolipid); U.S. Pat. No. 5,814,659 (Topical analgesic, alcohol, chaotropic agent (e.g. urea), unsaturated fatty acid); U.S. Pat. No. 5,635,205 (Anesthetic composition with triglycerides and amphipathic ligand, e.g. phospholipid); U.S. Pat. No. 3,949,071 (Burn treatment, aqueous buffer pH 8-10, base, surface active agent, fatty acid and lidocaine); 2006/0280801 (Analgesic, fatty acid metal salts and other components); 2006/0222687 (Topical anesthetic formulation includes lidocaine and fatty acids as penetration enhancers); 2004/0228884 (Ion pair composition releases active ingredient); 2004/0214215 (Molecular complex of alkaline drug and related acid); 2004/0058994 (Surgical wounds treated with lidocaine free base or salt, includes some carboxylic acids as exemplary); and 2003/0027833 (Anesthetics (includes lidocaine) and penetration enhancers (fatty acids)). (All of these references are incorporated herein by reference to the extent that the references describe methods of preparation of salts and use of the anesthetics.)
While not specifically directed to anesthetics, an extensive patent effort has been directed by Idexx Laboratories toward the use of fatty acid salts of amine drugs as slow release compositions. Idexx Laboratories have filed U.S. Pat. Nos. 7,033,599; 6,946,137; 6,887,487; 2007/0141162; and 2005/0075296, disclosing bupivacaine as one of the drugs.
The rapid loss of anesthetic effect is shown in the following table. (emedicine.com/ent/topic20.htm; eMedicine Specialties>Otolaryngology and Facial Plastic Surgery>PHARMACOLOGY). To extend the anesthetic effect, epinephrine is employed for vasoconstriction. The data demonstrate the need and desirability to provide an increased duration for the anesthesia.
Maximum DoseDurationOnset(with Epinephrine)(with Epinephrine)LidocaineRapid4.5 mg/kg(7 mg/kg)120 min(240 min)MepivacaineRapid5 mg/kg(7 mg/kg)180 min(360 min)BupivacaineSlow2.5 mg/kg(3 mg/kg)4 hours(8 h)RopivacaineMedium2-3 mg/kg3 hours(6 h)LevobupivacaineMedium2.0 mg/kg or 400 mg4-6 hours(8-12 h)in 24 hrsProcaineSlow8 mg/kg(10 mg/kg)45 min(90 min)ChloroprocaineRapid10 mg/kg(15 mg/kg)30 min(90 min)EtidocaineRapid2.5 mg/kg(4 mg/kg)4 hours(8 h)PrilocaineMedium5 mg/kg(7.5 mg/kg)90 min(360 min)TetracaineSlow1.5 mg/kg(2.5 mg/kg)3 hours(10 h)
As evidenced from the above, there have been extensive efforts to provide anesthetics with improved properties. The efforts have entailed the use of numerous polymeric matrices to provide for extended activity of the anesthetic due to the relatively short period that the anesthetics are effective. Alternatively, other investigations have been directed to additives that will enhance the effectiveness of the anesthetics in a variety of contexts. For treatment of wounds, particularly associated with surgery or other disruption of the skin resulting in severe pain, there is a need for a simple, safe and effective anesthetic that is long lasting and can easily be administered and produced.